Practice question

Assembly and activation of APC/C-Cdc20 must occur only after CDK1 has driven mitotic entry, ensuring anaphase does not initiate prematurely. During G2, APC/C exists in unphosphorylated inactive conformation with weak affinity for Cdc20, while Cdc20 itself is kept inactive by CDK inhibitory phosphorylation and binding to checkpoint protein Mad2. Upon entry into mitosis, cyclin B-CDK1, the master mitotic kinase, phosphorylates multiple subunits including APC1 at loop region, APC3, and APC6, inducing conformational rearrangement exposing C-box binding groove. Polo-like kinase Plk1 adds further phosphorylations enhancing Cdc20 docking. This priming step does not yet trigger substrate destruction because mitotic checkpoint complex still occupies Cdc20 until chromosome biorientation. Once checkpoint satisfied, pre-phosphorylated APC/C-Cdc20 unleashes polyubiquitination of securin and cyclin B. This dependency couples kinase surge to proteolysis, guaranteeing that chromosome condensation and spindle formation precede sister chromatid separation, preserving order of mitotic events. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.